Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.C([Mg]Cl)(C)C.[Cl-].[Li+].CON(C)[C:18](=[O:29])[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[N:21][CH:20]=1>C1COCC1>[CH3:7][N:6]1[C:2]([C:18]([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:23][CH:24]=2)=[O:29])=[CH:3][N:4]=[CH:5]1
Reactant: CON(C)C(=O)c1ccc(C(F)(F)F)nc1
Reactant: Cn1cncc1Br
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1cncc1C(=O)c1ccc(C(F)(F)F)nc1
Temperature: 5.300000190734863 °C
Reaction time: 1 h

Procedure:
To a 3 L 4-neck flask equipped with an overhead stirrer, nitrogen bubbler, and thermocouple was added 5-bromo-1-methyl-1H-imidazole (47.96 g, 297.9 mmol), followed by THF (537 mL). To this room temperature solution was added isopropylmagnesium chloride/lithium chloride complex (246.8 mL, 320.8 mmol, 1.3 M in THF) (addition temperature maintained between 16.6 and 25° C.) to afford a milky suspension and the reaction was stirred for 60 minutes and then cooled to 5.3° C. in an ice bath. To this mixture was added a solution of N-methoxy-N-methyl-6-(trifluoromethyl)nicotinamide (53.66 g, 229.14 mmol, Intermediate 2, step b) in THF (268.3 mL) (addition temperature between 5.3 and 5.6° C.) to afford an orange mixture. After addition, the reaction was warmed to room temperature over 2 hours. After stirring at room temperature for 18 hours, THF (200 mL) was added and the reaction was stirred for 2 hours. The reaction was then cooled to 4° C. with an ice bath and carefully quenched with 2 N aqueous HCl to pH=7, quenching temperature reached 12° C. The mixture was diluted with ethyl acetate (500 mL), phase separated and the organic layer was washed with brine (2×200 mL) and dried over sodium sulfate, filtered and the solvent was removed. Hot ether was added and then filtered to give the title compound as a solid.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=1)=O)(C)(C)C.Cl.O.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:10]2[S:11][CH:12]=[CH:13][C:9]=2[NH2:8])=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)Nc1ccsc1-c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ccsc1-c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7476 %

Procedure:
A solution of (tert-butoxy)-N-[2-(4-bromophenyl)(3-thienyl)]carboxamide (10.8 g, 0.3 mmol, preparation 7) in ethyl acetate (75 mL) at 0° C., is treated dropwise with 244 mL (8 mL/mmol) of freshly prepared 1N HCl in ethyl acetate and the mixture is stirred at room temperature overnight. The white precipitate is dissolved with H2O (100 mL) and neutralized with a NaHCO3 saturated solution. The mixture is then extracted with ethyl acetate (3×100 mL) and the combined organics are dried and concentrated to give a slightly colored solid. Purification of the crude material by flash chromatography (Silica gel-Hexane/AcOEt 49:1 then 9:1) furnishes 5.7 g (74%) of title compound as a pale yellow solid.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH:14]3[CH2:19][C:18]([CH3:21])([CH3:20])[NH:17][C:16]([CH3:23])([CH3:22])[CH2:15]3)[N:8]=2)=[CH:4][CH:3]=1.[CH3:24][C:25]([OH:29])([C:27]#[CH:28])[CH3:26]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:24][C:25]([OH:29])([C:27]#[C:28][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH:14]3[CH2:19][C:18]([CH3:21])([CH3:20])[NH:17][C:16]([CH3:23])([CH3:22])[CH2:15]3)[N:8]=2)=[CH:4][CH:3]=1)[CH3:26]
Reactant: CC1(C)CC(Nc2nccc(-c3ccc(Br)s3)n2)CC(C)(C)N1
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC(C)(O)C#Cc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)s1

Procedure:
{4-[5-Bromothiophen-2-yl]-pyrimidin-2-yl}-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine, described in Example 5, (300 mg, 0.76 mmol), PdCl2(PPh3)2 (18 mg, 0.025 mmol), 2-methyl-but-3-yn-2-ol (0.3 ml, 2.53 mmol) and CuI (15 mg) were dissolved in triethylamine (25 ml) and refluxed for 1 hour. The reaction mixture was evaporated, taken up in water and extracted 3 times with TBME. The combined organic phases were dried over sodium sulfate, filtered, and purified via chromatography on silicagel (DCM/MeOH/ammonia:95/5/1 to 90/10/1) to give the title compound as white solid, which was crystallized as HCl-salt from EtOH/HCl. Yield: 150 mg (32%).
Reaction SMILES: O[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([OH:12])=[CH:9][CH:8]=[CH:7]2.[C:13](=[O:16])([O-])[O-].[K+].[K+].[CH3:19][O:20][CH2:21]Cl>CC(C)=O>[CH3:19][O:20][CH2:21][O:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:2]([CH:13]=[O:16])=[CH:3][CH:4]=[CH:5]2
Reactant: COCCl
Reactant: Oc1cccc2cccc(O)c12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCOc1cccc2cccc(C=O)c12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
9.5 g of 8-hydroxy-1-naphthol was dissolved in 210 ml of acetone, to which 22.7 g of hydrous potassium carbonate and 5.43 ml of chloromethyl methyl ether were added and refluxed for one hour under heating. The reaction solution was filtered and the filtrate was concentrated. 12.2 g of thus obtained yellow oily product was dissolved with no further purification into 250 ml of dichloromethane, to which 4.3 g of pyridinium trifluoro acetate and 18.3 g of pyridinium dichromate were added and stirred at a room temperature for 12 hours. After filtering off insoluble matters, the filtrate was concentrated and then purified on silica gel column chromatography (10% ethyl acetatemexane), to obtain in 5.1 g of the above-captioned compound as colorness crystals.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:8][O:9][C:10]=2[C:11]([F:14])([F:13])[F:12])[N:3]=[CH:2]1.Cl[C:22]1[N:27]=[CH:26][CH:25]=[CH:24][N:23]=1>>[C:15]1([C:7]2[C:6]([C:4]3[N:3]=[CH:2][N:1]([C:22]4[N:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[CH:5]=3)=[C:10]([C:11]([F:14])([F:12])[F:13])[O:9][N:8]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: FC(F)(F)c1onc(-c2ccccc2)c1-c1c[nH]cn1
Reactant: Clc1ncccn1
Product: FC(F)(F)c1onc(-c2ccccc2)c1-c1cn(-c2ncccn2)cn1
Yield: 35 %

Procedure:
As described for Example 4, 4-(1H-imidazol-4-yl)-3-phenyl-5-trifluoromethyl-isoxazole (67.4 mg, 0.48 mmol) was converted, using 2-chloropyrimidine instead of 4-fluorobenzotrifluoride, to the title compound (40 mg, 35%) which was obtained as a white solid. MS: m/e=358.2 [M+H]+.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH2:15][CH2:16][Cl:17])=[CH:8][C:7]=1[CH2:18][O:19]C(=O)C)(=O)C.N>CO>[Cl:17][CH2:16][CH2:15][O:14][C:9]1[C:10]([O:12][CH3:13])=[CH:11][C:6]([CH2:5][OH:4])=[C:7]([CH2:18][OH:19])[CH:8]=1
Reactant: COc1cc(COC(C)=O)c(COC(C)=O)cc1OCCCl
Agent: N
Solvent: CO
Product: COc1cc(CO)c(CO)cc1OCCCl
Reaction time: 15 h
Yield: 94.5 %

Procedure:
A solution of 14.0 g of the 2-[(acetyloxy)methyl]-4-(2-chloroethoxy)-5-methoxybenzyl acetate in 600 mL of methanol is stirred and cooled in an ice bath while ammonia gas is bubbled in, until the solution is saturated. The flask is stoppered and stored in the refrigerator for 15 hours. The reaction mixture is evaporated to give a white solid which is dried and chromatographed on a silica gel column eluting with 2:1 hexanes/ethyl acetate, to give 9.87 g of [4-(2-chloroethoxy)-2-(hydroxymethyl)-5-methoxyphenyl]methanol as a white solid, m.p. 93-4° C.
Reaction SMILES: O.O.[Sn](Cl)Cl.[CH3:6][O:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]([N+:19]([O-])=O)=[C:14]2[O:18][CH:17]=[CH:16][C:15]=12)=[O:9]>C(OCC)(=O)C.C(O)C>[CH3:6][O:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]([NH2:19])=[C:14]2[O:18][CH:17]=[CH:16][C:15]=12)=[O:9]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c2occc12
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccc(N)c2occc12
Temperature: 25 °C
Reaction time: 96 h
Yield: 88.1 %

Procedure:
Tin (II) chloride dihydrate (15.0 g, 66.5 mmol) was added to a suspension of 7-nitro-benzofuran-4-carboxylic acid methyl ester (4.82 g, 21.8 mmol) in ethyl acetate (80 mL) and ethanol (80 mL). The reaction mixture was stirred at room temperature for four days then partitioned between ethyl acetate and saturated aqueous solution of potassium carbonate. The organic extract was washed with brine, dried (anhydrous sodium sulfate) and concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel eluting with 30% ethyl acetate in hexane give 7-amino-benzofuran-4-carboxylic acid methyl ester (3.67 g, 88%). 1H NMR (CDCl3) δ: 3.92 (s, 3H), 6.60 (d, 1H, J=8.2 Hz), 7.34 (d, 1H, J=2.1 Hz), 7.67 (d, 1H, J=2.1 Hz), 7.84 (d, 1H, J=8.2 Hz).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[S:8]([OH:11])(=O)=[O:9].P(Cl)(Cl)([Cl:14])=O.P(Cl)(Cl)Cl.ClCl.[ClH:23]>>[Cl:23][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[S:8]([Cl:14])(=[O:11])=[O:9]
Reactant: O=S(=O)(O)c1cnccc1O
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cl
Agent: ClCl
Solvent: ClP(Cl)Cl
Product: O=S(=O)(Cl)c1cnccc1Cl
Temperature: 80 °C
Reaction time: 3 h

Procedure:
There are taken 1137.5 g (6.49 mol) 4-hydroxy-pyridine-3-sulphonic acid, 3481 g (2085 ml/22.7 mol) phosphorus oxychloride and 2115 g (1345 ml/15.4 mol) phosphorus trichloride and heated to reflux with stirring, whereby the sump temperature increases to about 80° C. In about 3 hours, 1092 g (15.4 mol) chlorine gas are passed into the reaction mixture which is immediately taken up by the mixture. With HCl evolution, the sump temperature increases to about 100° C. After 24 hours under reflux, whereby the sump temperature increases to 110° C. into the boiling range of the phosphorus oxychloride, the mixture becomes almost clear. 5550 g (3313 ml) phosphorus oxychloride are distilled off under water pump vacuum and can be reused. The residue is taken up at about 40° C. with 5030 g (4000 ml) ethylene chloride and, with external water cooling, mixed portionwise with 2600 ml water at a maximum of 30° C. After separation of the phases, the organic phase is stirred up twice with, in each case, 2500 ml water. By distilling off of the solvent and drying in a vacuum, the 4-chloropyridine-3-sulphonic acid chloride can be isolated in practically quantitative yield.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[NH2:20][C:21]1[C:26]([Br:27])=[CH:25][C:24]([SH:28])=[CH:23][C:22]=1[Br:29]>>[NH2:20][C:21]1[C:26]([Br:27])=[CH:25][C:24]([S:28][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=3[CH:19]=2)=[CH:23][C:22]=1[Br:29]
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCl)cc21
Reactant: Nc1c(Br)cc(S)cc1Br
Product: CC1(C)OC(=O)Nc2ccc(OCCCCSc3cc(Br)c(N)c(Br)c3)cc21

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-amino-3,5-dibromo-thiophenol.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[O:5][CH:6]=[CH:7][CH:8]=1.N1C=CN=C1.[CH3:14][C:15]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])[CH3:16].C(OCC)C>CN(C=O)C>[CH3:14][C:15]([Si:18]([CH3:20])([CH3:19])[O:1][CH2:2][CH2:3][C:4]1[O:5][CH:6]=[CH:7][CH:8]=1)([CH3:17])[CH3:16]
Reactant: OCCc1ccco1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCc1ccco1
Reaction time: 2 h

Procedure:
2-(2-Hydroxyethyl)furan (1.00 g, 8.93 mmol, Example 255A) was dissolved in DMF at 25° C. and imidazole (0.790 g, 11.6 mmol) was added. TBSCl (1.35 g, 8.93 mmol) was then added in portions over 5 minutes. After 2 h, the reaction was poured into diethyl ether (300 mL) and washed sequentially with water (1×100 mL), 1 N HCl (1×100 mL), and brine (1×100 mL). The combined organics were then dried over magnesium sulfate and concentrated in vacuo. Compound 241A was isolated as a clear oil (1.77 g) and was taken on without purification. HPLC: 100% at 4.233 min (retention time) (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).
Reaction SMILES: I.[F:2][C:3]1[CH:4]=[C:5]([NH:15][C:16](SC)=[NH:17])[CH:6]=[CH:7][C:8]=1[N:9]1[C:13]([CH3:14])=[N:12][CH:11]=[N:10]1.[Cl:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]([F:40])([F:39])[F:38])=[CH:31][CH:30]=1)[C:26](O)=O.CN1CCOCC1.C(N(CC)C(C)C)(C)C.[NH2:57][NH2:58]>>[Cl:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([C:26]1[NH:58][N:57]=[C:16]([NH:15][C:5]2[CH:6]=[CH:7][C:8]([N:9]3[C:13]([CH3:14])=[N:12][CH:11]=[N:10]3)=[C:3]([F:2])[CH:4]=2)[N:17]=1)[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]([F:38])([F:39])[F:40])=[CH:31][CH:30]=1
Reactant: NN
Reactant: O=C(O)C(CCCCCl)c1ccc(OCC(F)(F)F)cc1
Reactant: CSC(=N)Nc1ccc(-n2ncnc2C)c(F)c1
Agent: I
Solvent: CN1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncnn1-c1ccc(Nc2n[nH]c(C(CCCCCl)c3ccc(OCC(F)(F)F)cc3)n2)cc1F
Yield: 102.9 %

Procedure:
Methyl 3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenylcarbamimidothioate, hydroiodide (1.50 g, 3.81 mmol, from preparation C) and 6-chloro-2-(4-(2,2,2-trifluoroethoxy)phenyl)hexanoic acid (1.30 g, 4.00 mmol, from preparation AW) were coupled [N-methylmorpholine (2.10 mL, 19.1 mmol) was substituted for N,N-diisopropylethylamine] and then reacted with hydrazine (0.598 mL, 19.1 mmol) using a procedure analogous to Step A of Example 13. After an aqueous workup, 5-(5-chloro-1-(4-(2,2,2-trifluoroethoxy)phenyl)pentyl)-N-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-1H-1,2,4-triazol-3-amine (2.11 g, 3.92 mmol, quantitative yield) was obtained as a brown foamy solid. The crude product was used in the next step without purification. LC-MS (M+H)+ 538.4.
Reaction SMILES: [C:1]1([CH2:7][C:8](=O)[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:11]([NH2:13])=[O:12]>C(O)=O>[CH:11]([NH:13][CH:8]([CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:9])=[O:12]
Reactant: CC(=O)Cc1ccccc1
Reactant: NC=O
Solvent: O=CO
Product: CC(Cc1ccccc1)NC=O
Yield: 60 %

Procedure:
Many methods of making amphetamine and related compounds are known in the prior art, including the commercially used Leukart-Wallach reaction for producing racemic amphetamine from phenylacetone. For example, in one commercial process, phenylacetone is reacted with formamide and formic acid to form (±)-N-formylamphetamine (racemic N-formylamphetamine). The racemic N-formylamphetamine is then hydrolyzed with sulfuric acid, the solution basified, and the resulting d,l-amphetamine ((±)-amphetamine; racemic amphetamine) is distilled with an overall yield of about 60%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([NH:15][CH:16]([CH3:18])[CH3:17])=[O:14])[CH:11]=2)[NH:6][CH:5]=1.C[OH:20].[C:21]([O:24][CH2:25][CH3:26])(=[O:23])[CH3:22]>>[CH3:17][CH:16]([NH:15][C:13]([C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[NH:6][CH:5]=[C:4]2[CH2:3][CH2:2][NH:1][C:21](=[O:23])[O:24][CH2:25][C:26]1[CH:11]=[CH:12][CH:4]=[CH:3][CH:2]=1)=[O:14])[CH3:18].[C:13]([O-:14])(=[O:20])/[CH:10]=[CH:22]\[C:21]([O-:24])=[O:23]
Reactant: CC(C)NC(=O)c1ccc2[nH]cc(CCN)c2c1
Reactant: CCOC(C)=O
Reactant: CO
Product: CC(C)NC(=O)c1ccc2[nH]cc(CCNC(=O)OCc3ccccc3)c2c1
Product: O=C([O-])/C=C\C(=O)[O-]

Procedure:
(ii)b [2-[5-[[(1-Methylethyl)amino]carbonyl]1H-indol-3-yl]ethyl carbamic acid, phenylmethyl ester (0.4 g) gave 3-(2-aminoethyl)-N-(1-methylethyl)-1H-indole-5-carboxamide, maleate (0.25 g) as a white crystalline solid m.p. 174°-5° C. (from methanol/ethyl acetate)
Reaction SMILES: [I:1][C:2]1[C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=2)=[N:4][NH:5][CH:6]=1.[C:16](=[O:19])([O-])[O-].[Cs+].[Cs+].[Cl-].O>CN(C)C=O>[I:1][C:2]1[C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=2)=[N:4][N:5]([CH2:3][C:7]2[CH:12]=[CH:11][C:10]([O:19][CH3:16])=[CH:9][CH:8]=2)[CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1cccc(-c2n[nH]cc2I)c1
Agent: [Cl-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc(I)c(-c3cccc([N+](=O)[O-])c3)n2)cc1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
2 g (6.3 mmol) of 4-iodo-3-(3-nitrophenyl)-1H-pyrazole were dissolved in 20 ml of dry dimethylformamide and 2.46 g (7.5 mmol) of cesium carbonate and 0.85 ml (6.3 mmol) of p-methoxybemzyl chloride were added successively. The reaction mixture was heated at 70° C. under stirring for 5 hours. Water was then added and the product extracted with dichloromethane. The organic phase was dried over sodium sulphate and the solvent evaporated under reduced pressure. 2.4 g (86%) of the title compound crystallized from a mixture diethylether-diisopropylether.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]([O:16][CH3:17])=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O>[Pd].C(O)C.ClCCl>[NH2:1][C:4]1[CH:5]=[C:6]([C:14]([O:16][CH3:17])=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: COC(=O)c1cc([N+](=O)[O-])cc2ccccc12
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: COC(=O)c1cc(N)cc2ccccc12
Reaction time: 3 h

Procedure:
To 1.15 g (1.08 mmol) of 10% palladium on carbon was added a suspension of 11.6 g (50.0 mmol) of the above methyl 3-nitro-1-naphthoate in 150 mL of anhydrous ethanol and 40 mL of anhydrous dichloromethane. The resulting suspension was agitated under an atmosphere of hydrogen at 40 psi for 3 h during which time all solids dissolved. The reaction mixture was filtered through a plug of Celite®, which was subsequently washed with dichloromethane (300 mL). The combined filtrates were concentrated in vacuo to yield the title compound as a pale green gum which was used without further purification. LC/MS 202.1 (N+1).
Reaction SMILES: CS[C:3](=[O:14])[C:4]([C:6]1[N:7]=[C:8]([NH:11][CH:12]=[O:13])[S:9][CH:10]=1)=[O:5].[OH-:15].[Na+].Cl>O>[CH:12]([NH:11][C:8]1[S:9][CH:10]=[C:6]([C:4](=[O:5])[C:3]([OH:14])=[O:15])[N:7]=1)=[O:13]
Reactant: [OH-]
Reactant: CSC(=O)C(=O)c1csc(NC=O)n1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=CNc1nc(C(=O)C(=O)O)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.6 %

Procedure:
In 200 ml of water is suspended 23 g of 2-(2-formylaminothiazol-4-yl)thioglyoxylic S-acid methyl ester, and 125 ml of a 2 N aqueous sodium hydroxide solution was added thereto dropwise with water-cooling over a period of 30 minutes, after which the resulting mixture was stirred at room temperature for 1 hour. After completion of the reaction, the thus obtained reaction mixture was adjusted to pH 2.5 with 6 N hydrochloric acid. The deposited crystals were collected by filtration, washed successively with water and acetone, and then dried to obtain 16.2 g (81.6% yield) of 2-(2-formylaminothiazol-4-yl)glyoxylic acid having a melting point of above 210° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5].IC.[C:15](=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O>[CH3:15][O:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])cc1C=O
Reaction time: 24 h

Procedure:
2-Hydroxy-5-nitrobenzaldehyde (2.40 g, 14.0 mmol) was dissolved in dimethylformamide (50 mL). To this was added iodomethane (4.48 ml, 72.0 mmol) and sodium carbonate (3.04 g, 28.0 mmol). This mixture was stirred for 24 hours and was poured into water. The solid was collected by filtration to give 2.38 g (93.0%). Mp 88-89° C.;1H NMR (CDCl3): d, 10.46 (s,1H), 8.69 (d,1H), 8.45 (dd,1H), 7.15 (d,1H), 4.10 (s,3H). MS (DCl): 182 (MH+). C8H7NO4.
Reaction SMILES: CCCCC/C=C/C[CH2:9][C:10]([NH:12][CH:13]1[CH:18]([O:19][C:20]2[C:25]3[O:26][C:27]4[CH:32]=[CH:31][C:30]([CH:33]([O:116][CH:117]5[O:122][CH:121]([CH2:123][OH:124])[CH:120]([OH:125])[CH:119]([OH:126])[CH:118]5[NH:127][C:128]([CH3:130])=[O:129])[CH:34]5[NH:54][C:52](=[O:53])[CH:51]([NH:55][C:56]([CH:58]6[NH:59][C:60]([CH:62]7[NH:95][C:93](=[O:94])[CH:82]([CH:83](O)[C:84]8[CH:90]=[CH:89][C:87]([O:88][C:21]=2[CH:22]=[C:23]6[CH:24]=3)=[C:86]([Cl:91])[CH:85]=8)[NH:81][C:79](=[O:80])[CH:78]([NH2:96])[C:76]2=[CH:77][C:72](=[C:73]([OH:97])[CH:74]=[CH:75]2)[O:71][C:65]2=[C:66](C)[C:67]([OH:69])=[CH:68][C:63]7=[CH:64]2)=[O:61])=[O:57])[C:49]2=[CH:50][C:45](=[C:46]([OH:98])[CH:47]=[CH:48]2)[C:44]2[C:39](=[CH:40][C:41]([OH:111])=[CH:42][C:43]=2[O:99][CH:100]2[O:105][CH:104]([CH2:106][OH:107])[CH:103]([OH:108])[CH:102]([OH:109])[CH:101]2[OH:110])[CH:38]([C:112]([O:114]C)=[O:113])[NH:37][C:35]5=[O:36])=[CH:29][C:28]=4[Cl:131])[O:17][CH:16]([CH2:132][OH:133])[CH:15]([OH:134])[CH:14]1[OH:135])=[O:11]>Cl>[CH3:9][C:10]([NH:12][C@@H:13]1[C@H:18]([O:19][C:20]2[C:25]3[O:26][C:27]4[CH:32]=[CH:31][C:30]([C@@H:33]([O:116][C@@H:117]5[O:122][C@@H:121]([CH2:123][OH:124])[C@@H:120]([OH:125])[C@H:119]([OH:126])[C@@H:118]5[NH:127][C:128]([CH3:130])=[O:129])[C@@H:34]5[NH:54][C:52](=[O:53])[C@H:51]([NH:55][C:56]([C@@H:58]6[NH:59][C:60]([C@H:62]7[NH:95][C:93](=[O:94])[C@@H:82]([CH2:83][C:84]8[CH:90]=[CH:89][C:87]([O:88][C:21]=2[CH:22]=[C:23]6[CH:24]=3)=[C:86]([Cl:91])[CH:85]=8)[NH:81][C:79](=[O:80])[C@H:78]([NH2:96])[C:76]2[CH:75]=[CH:74][C:73]([OH:97])=[C:72]([CH:77]=2)[O:71][C:65]2=[CH:64][C:63]7=[CH:68][C:67]([OH:69])=[CH:66]2)=[O:61])=[O:57])[C:49]2[CH:48]=[CH:47][C:46]([OH:98])=[C:45]([CH:50]=2)[C:44]2[C:43]([O:99][C@H:100]3[O:105][C@H:104]([CH2:106][OH:107])[C@@H:103]([OH:108])[C@@H:102]([OH:109])[C@@H:101]3[OH:110])=[CH:42][C:41]([OH:111])=[CH:40][C:39]=2[C@@H:38]([C:112]([OH:114])=[O:113])[NH:37][C:35]5=[O:36])=[CH:29][C:28]=4[Cl:131])[O:17][C@@H:16]([CH2:132][OH:133])[C@@H:15]([OH:134])[C@@H:14]1[OH:135])=[O:11]
Reactant: CCCCC/C=C/CCC(=O)NC1C(Oc2c3cc4cc2Oc2ccc(cc2Cl)C(OC2OC(CO)C(O)C(O)C2NC(C)=O)C2NC(=O)C(NC(=O)C4NC(=O)C4NC(=O)C(NC(=O)C(N)c5ccc(O)c(c5)Oc5cc4cc(O)c5C)C(O)c4ccc(c(Cl)c4)O3)c3ccc(O)c(c3)-c3c(OC4OC(CO)C(O)C(O)C4O)cc(O)cc3C(C(=O)OC)NC2=O)OC(CO)C(O)C1O
Agent: Cl
Product: CC(=O)N[C@@H]1[C@H](Oc2c3cc4cc2Oc2ccc(cc2Cl)[C@@H](O[C@@H]2O[C@@H](CO)[C@@H](O)[C@H](O)[C@@H]2NC(C)=O)[C@@H]2NC(=O)[C@H](NC(=O)[C@@H]4NC(=O)[C@H]4NC(=O)[C@@H](Cc5ccc(c(Cl)c5)O3)NC(=O)[C@H](N)c3ccc(O)c(c3)Oc3cc(O)cc4c3)c3ccc(O)c(c3)-c3c(O[C@H]4O[C@H](CO)[C@@H](O)[C@@H](O)[C@@H]4O)cc(O)cc3[C@@H](C(=O)O)NC2=O)O[C@@H](CO)[C@@H](O)[C@@H]1O

Procedure:
Teicoplanin A2 (10 g) is added to 1 N hydrochloric acid (150 ml) preheated to 80° C. while stirring. After about 45 minutes the reaction mixture is cooled to 0°-5° C. and 37% hydrochloric acid (30 ml) is added. Stirring is maintained for about 10 minutes, after which the precipitated solid is recovered by filtration, washed with 20 ml of 2 N HCl, then with ethyl ether, and dried overnight over potassium hydroxide pellets at room temperature, resulting in the crude product of the title (8.3 g).
Reaction SMILES: [O:1]=[C:2]([CH3:5])[CH:3]=[CH2:4].[CH3:6][NH:7][CH2:8][CH2:9][CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(OCC)C>[CH3:6][N:7]([CH2:8][CH2:9][CH:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:4][CH2:3][C:2](=[O:1])[CH3:5]
Reactant: CNCCC(c1ccccc1)c1ccccc1
Reactant: C=CC(C)=O
Solvent: CCOCC
Product: CC(=O)CCN(C)CCC(c1ccccc1)c1ccccc1
Yield: 100 %

Procedure:
A solution of 3.72 ml of 3-oxo-but-1-ene was added dropwise, over a period of 20 minutes and such that the temperature did not exceed 2°-3° C., to a cooled solution of 7.87 g of N-methyl-3,3-diphenylpropylamine in 7 ml of diethyl ether. The solution thus obtained was evaporated in vacuo at room temperature to give 10.3 g of N-methyl-N-(3,3-diphenylpropyl)-4-aminobutan-2-one (100%) as free base, shown to be practically pure by TLC (chloroform:methanol 9:1 by volume) which could be used as such for further reactions. This compound could be transformed into the corresponding hydrochloride (m.p. 133°-135° C.) by treating the free base with hydrogen chloride in diethyl ether, and crystallizing the product thus obtained first from acetone:ethyl acetate:isopropanol then from acetone.